These transgenic mice express the mutant A53T human alpha-synuclein (SNCA) under the direction of the mouse prion protein promoter in nigrostriatal and corticostriatal projection neurons, but not local striatal neurons. The A53T mutation is associated with
early onset familial Parkinson's disease. Transgene expression levels are 1.5-2 fold greater than endogenous mouse gene expression levels. Homozygotes older than 6 months of age display progressively spontaneous vertical movement (rearing). At 7 months of age, dense alpha-synuclein immunoreactive resembling Lewy neurites is detected in the olfactory bulb. Ultrastructural examination of neurons reveals diffuse accumulation of human alpha-synuclein. A53T SCNA protein is detected in neuronal axons, dendrites, cell bodies, and nuclei throughout the CNS by immunohistochemical analysis (including: olfactory bulb, cerebral cortex, hippocampus, midbrain, pons, medulla oblongata). Mice 18 months of age and older display insoluble alpha-synuclein in nigrostriatal tissue together with an increase of 14-3-3 isoforms in striatum, elevated striatal dopamine levels, altered dopamine release, decreased transcript levels of the extraneural dopamine degradation enzyme COMT, upregulated striatal dopamine receptors, decreased postsynaptic dopamine response in Homer1 (homer homolog 1 (Drosophila)), Cb1 (cannabinoid receptor 1 (brain)) and Pde7b (phosphodiesterase 7B) transcript levels as well as impaired corticostriatal long term depression. Survival of homozygotes at 24 months of age is lower than survival of wildtype controls. Mice homozygous for the transgenic insert are viable, fertile, and normal in size.
